BACKGROUND: PUVA photochemotherapy is
indicated to treat mycosis fungoides, either as monotherapy in the earlier stages
of the disease or in combination with other drugs in more advanced stages of
evolution. OBJECTIVES: To evaluate PUVA photochemotherapy response in patients with
mycosis fungoides. METHODS: From January 1996 to November 2003, 17 patients with a diagnosis
of mycosis fungoides were seen in the Dermatological Phototherapy Division of
Santa Casa de Sao Paulo, Brazil. PUVA treatment was carried out as monotherapy
at early stages of evolution and in combination with other treatments in more
advanced cases of mycosis fungoides. The treatment response was evaluated regarding
cutaneous clinical and histological improvement. RESULTS: Fourteen of 16 patients improved after PUVA. The rate of improvement
in skin after treatment related to the initial stage of disease presented as
follows: five patients (one in stage IA and four in IB) had total control (cure
of lesions); four (all IB) had major regression (improvement of 70%-99%);
two (IIB and IVA) had moderated improvement (50%-69%); three (IA, IB,
IIA) had mild regression (less than 50%); two (IB, IIB) were unaltered.
Only one patient had to discontinue treatment due to intense burning. CONCLUSION: Eighty-seven percent patients responded to PUVA therapy,
and 56% presented total control or significant improvement of lesions. The
effectiveness of treatment resulted in regression of lesions mainly in early
stage cases. PUVA photochemotherapy was a successful and safe treatment, making
it a good choice for patients with mycosis fungoides.

Skin T cells are a dynamic population of lymphocytes
with distinct surface cell markers. The malignant process of epidermotropic
T cells results in the condition generally defined as cutaneous T cell lymphoma
(CTCL). Therefore, CTCL represents a lymphoproliferative disease that originates
from malignant T cell clones due to changes in their apoptosis process.1,2

It is a non-Hodgkin lymphoma with various clinical
manifestations, which are frequently difficult to differentiate from one another.
There is a possibility of one form developing into another.3,4

Major variants of CTCL are grouped as: I) mycosis
fungoides and its various subdivisions; II) non-mycosis fungoides CTCL; III)
lymphoproliferative immunodeficiency disorder. Thus, mycosis fungoides is defined
as a subdivision of CTCL.5,6

Neoplastic cells of mycosis fungoides correspond
to clones of memory T cells that migrate to the superficial dermis and epidermis,
which favors the use of skin-oriented therapies.7-15

The treatment of CTCL is still controversial,
and various therapeutic methods are proposed to approach it, without an actual
consensus on the best treatment to be used. Data from the literature show that
successful treatment depends directly on the development phase in which the
disease is, besides each patients individual response. The earlier the therapeutic
approach, the better the prognosis.7

Finally, worth of mention is photochemotherapy
with PUVA, the object of the present study. The method consists of irradiation
of the skin with ultraviolet A rays that is associated with the oral use of
psoralen, thus having a phototoxic effect on the skin. PUVA acts mainly as an
antiproliferative agent on T lymphocytes (TL).

The present study aims to: 1) characterize the
group of patients with mycosis fungoides according to sex, color and disease
staging; 2) evaluate therapeutic response with photochemotherapy (PUVA) on these
patients, in the various stages of this skin condition.

MATERIAL AND METHODS

Seventeen patients with mycosis fungoides were
seen at the Dermatology Clinic of Santa Casa de Misericórdia de São Paulo from
January 1996 to November 2003. The diagnosis of mycosis fungoides was made by
means of clinical and pathological examination.

All patients were referred to the Hematology
Division for staging. To that end, the TNM (tumor-node-metastasis system) method
was used and adjusted to the CTCL specific parameters. Both local and systemic
clinical aspects and grading of the lesion, considering body surface affected
and lymph nodes involved, peripheral and visceral blood were taken into consideration
(Chart 1).

Treating with photochemotherapy was indicated
after staging. PUVA as monotherapy was indicated for patients in initial stages.
For more advanced stages, photochemotherapy was prescribed only as adjuvant
treatment, as an attempt to improve patients quality of life.

Photochemotherapy is an association of UVA radiation
and phototoxic effects of psoralen given orally, aiming to produce an immunosuppressant
effect on the skin. The specifications of the components of this treatment method
are as follows:

UVA radiation characteristics: Type A ultraviolet
radiation consists of light beams with wavelength ranging from 320 to 400nm.
The source of beams are special lamps placed in a one-square-meter cabin, in
which the patient is positioned in supine, and eyes protected by radiation filtering
glasses in order to avoid eye lesions. The power of the UVA radiation is directly
proportional to exposure time and measurement in Joules/cm2. Exposure
time varies according to patient phototype, individual response to treatment
and number of photochemotherapy sessions performed previously

Psoralen characteristics: the substance utilized
in the present study was 8-metoxipsoralen (8-MOP) in a concentration of 0.6mg/kg,
prescribed as syrup, given orally, 60 minutes before each phototherapy session.
The aim was to boost UVA-ray uptake by the skin, due to its phototoxic effects.
All patients were submitted to two or three weekly sessions, according to intensity
of the clinical picture.

Treatment results with photochemotherapy were
assessed according to clinical parameters of the aspect of skin lesions (macroscopic
improvement of infiltrative process, disappearance of erythema, absence of new
lesions). In cases with total clinical remission of lesions a new pathological
examination of the cutaneous region previously affected was performed. If histological
changes compatible to mycosis fungoides had disappeared, the disease was considered
under control.

All patients were followed up for a maximum period
of 12 months, when they were assessed regarding:

a) time necessary to begin improvement of skin
lesions;

b) minimum number of sessions to observe signs
of therapeutic response;

c) intensity of therapeutic response: the total
number of photochemotherapy sessions performed.

Patients were classified according to progression
of skin condition after treatment as:

1) unaltered (if there were no changes in skin
lesions);

2) with mild regression (if there was at least
50% of clinical improvement).

3) with moderate improvement (if there was at
least 50% to 69% of clinical improvement).

4) with major regression (if there was at least
70% a 99% of clinical improvement).

5) with total control of disease (if there was
100% of clinical improvement of skin lesions, in addition to pathological
examination with no evidence of the tumor).

The correlation between the therapeutic response
and initial staging of mycosis fungoides was also assessed.

RESULTS

The characteristics of the 17 patients selected
for the study are as follows. There were 10 female and seven male patients,
therefore with 59% predominance of women over 41% of men (Graph
1).

White was the most prevailing color, representing
76% (13) of patients. There were also three mulatto patients (18%) and
one black patient (6%) (Graph 2).

The age of patients treated ranged between 31
and 80 years: mean of 56.6 years.

Patients were submitted to disease staging at
the beginning of treatment, according to the TNM method, with the following
distribution: two patients (12%) were classified as IA; 11 (64%) as
IB; one (6%) as IIA; two (12%) as IIB; and one (6%) as IVA (Graph
3).

Treatment time until the beginning of lesion
improvement ranged from one to six months. There was also 70% (12 out of
17 patients) who reached initial response in up to two months of treatment.

The minimum number of sessions until the beginning
of improvement ranged between three and 50 sessions, with a mean de 16 sessions.

The total number of phototherapy sessions ranged
between 13 and 136, with a mean of 57 sessions.

Sixteen patients were followed up during the
12-month period established. Total treatment time ranged from two to 12 months,
with a mean of seven months. One patient withdrew treatment due to intolerance
to the side effect of intense burning after PUVA applications. The remaining
16 patients ended the study as follows (Graph 4):

- five patients evolved to total disease control,
translated by total macroscopic remission of lesions and microscopic assessment,
by a pathological examination free of cell changes in the site previously registered
as with neoplastic changes;

- four attained major regression;

- two attained moderate improvement;

- three had mild regression;

- two patients remained with unaltered skin lesions.

Treatment results were analyzed according to
the initial stage of each patient at the time of diagnosis (Table
1).

Considering the five patients who attained "total
control" of the disease, one was IA stage, and four stage IB, that is, all had
initial stage disease.

All four patients with "major regression" were
stage IB, also with localized disease, in an initial phase.

Regarding the two patients with "moderate improvement",
one was stage IIB, and one stage IVA (disseminated disease).

The three patients with "mild regression" were
stage IA, IB and IIA, that is, both patients in an initial phase and in an already
invasive form of the disease.

As to the two unaltered patients, one was stage
IB, and the other was IIB.

DISCUSSION

Mycosis fungoides is a type of primary skin lymphoma
more common in the general population, totaling 39% of skin lymphomas. An
incidence of 0.5 cases/100000 individuals/year was described, and the mean age
of patients affected was approximately 56 years.10,11 Therefore,
mycosis fungoides is considered a rare disease in the population, and that is
probably the reason for being difficult to epidemiologically characterize this
specific non-Hodgkin lymphoma. In 1999, Weinstock et al. published a study showing
an incidence of 0.36 cases/100000 individuals/year, between 1973 and 1992. The
authors concluded that the incidence rate has been stable throughout the years
and that the mortality rate has decreased.12,13 Another Spanish study,
by Morales Suarez-Varela et al., published in 2000, suggested that the incidence
of mycosis fungoides cases has grown throughout the years, although the authors
considered that the data could represent an mistake, given the concomitant improvement
of diagnostic techniques. Few risk factors were identified, but an association
with industrial exposure, especially to oils was noticed. A higher risk for
developing mycosis fungoides was observed for men and black individuals.14
A Tunisian study verified prevailing female gender.11

In the present study, there were 59% of women,
therefore a slight dominance of the gender.

Seventy-six per cent of patients were white,
different from what was observed in the literature.

The mean age of patients, at the time of the
mycosis fungoides diagnosis was 56.6 years, similar to the findings in the literature.

As to the disease stage at the time of diagnosis,
of the 17 patients studied,13 (76%) were at stages IA and IB of mycosis
fungoides; three (18%) between stages IIA and IIB; one (6%) had an invasive
form of the disease (stage IVA), characterized by the variant called Sézary
syndrome.

The nine (53%) patients with a totally controlled
disease or improvement of a minimum of 70% of lesions were initially stages
IA and IB, representing 69% of the category. The other four patients fit
into stages IIA, IIB and IVA, but, although having a more severe form of the
disease, 75% of them (three patients) had a moderate to mild improvement
with treatment. Based on the cases of the present study, patients in initial
stages of the disease were more frequent and were exactly those who benefited
from photochemotherapy. The results of the present research, like those reported
in the literature, make us believe that the therapeutic efficacy of photochemotherapy
with PUVA for mycosis fungoides cases depends mainly on the initial stage of
the disease; however, even in more advanced cases, this therapeutic option proved
to be useful to reduce symptoms of patients studied.

Of the total 16 patients who completed treatment,
14 (87%) had some therapeutic response, with some level of benefit when
submitted to photochemotherapy. Of the 17 patients studied, one had intense
side effects, with a feeling of burning on lesions, enough to prevent him from
continuing treatment.

The mechanisms of action of PUVA therapy have
been well studied and defined in the literature. The efficacy of the treatment
would be linked both to the direct phototoxic power to destroy neoplastic cells
and the capacity of changing the production of cytokines, that is, an immunomodulatory
capacity of indirect effects to fight neoplastic cells.

The immunomodulatory action of PUVA therapy is
related to its capacity to act on inflammatory cytokines, on monocytes and neoplastic
T cells. It has been proven that CD4+ cells treated with PUVA produce
cytokines of IFN-gamma and IL-2 type Th1 cells, which, in turn, activate cytotoxic
CD8+ T lymphocytes, with direct antitumoral action. The same CD4+
cells simultaneously would stimulate monocytes to produce cytokines, such as
IL-8, and to transform themselves into efficient cells that present antitumor
antigen to cytotoxic CD8+ lymphocytes. Finally, cytotoxic CD8+
T lymphocytes would be responsible for lysis of neoplastic cells due to the
release of Th2 cytokines. Despite all that, the exact molecular mechanism by
which photochemotherapy would act on these cellular events has not as yet been
elucidated.11,16,-20

PUVA therapy has proven effective not only in
the sense of total neoplastic control or even prolonged disease remission, but
in its capacity to offer relevant improvement in quality of life of patients
treated. Improvement in the aspect of skin lesions, and the low rate of secondary
skin infections was provided to these patients, consequently favoring recovery
of their self-esteem and general well-being.21 A good level of treatment
compliance, due to easy administration, good cost/benefit ratio and few side
effects during treatment were verified. Still to be considered is the enormous
advantage of being able to restart treatment whenever necessary, given its low
toxicity. Its topical action on the neoplastic lesion also allows the association
with other therapeutic or systemic methods, if necessary, not interacting with
them in a deleterious fashion. For all these reasons, PUVA therapy was considered
a good therapeutic option for cases of mycosis fungoides reported in the literature,
and confirmed by the present study.

CONCLUSIONS

PUVA treatment was effective for 87% of
patients, of which 56% with total control or significant improvement of
the disease. Effectiveness was greater in the initial stages of the disease.
Photochemotherapy has proved to be safe and effective, with good patient compliance,
and therefore should be considered for individuals with mycosis fungoides.